Neurochemical Pattern Generation with Smart Electrical Stimulation Pedram Mohseni1 and Paul A. Garris2 1 Case Western Reserve University 2 Illinois State University In this Small Research Grant (Parent R03) proposal, an electrical engineer/computer scientist (PI Mohseni) and a neurobiologist/analytical chemist (PI Garris) will collaborate to develop the next generation of wireless neurochemical sensing integrated circuits (ICs) by incorporating the additional functionality of chemical pattern generation with electrical stimulation. Real-time chemical microsensors hold great promise for investigating brain function and pathology. Their defining analytical characteristic is the capability to interrogate the activity of a single neuron type, by virtue of identifying the released neurotransmitter. Perhaps the most monumental achievement to date with this measurement modality is dopamine monitoring with subsecond temporal resolution at a brain-implanted, micron-sized probe during goal-directed behavior using fast-scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM). Great strides have also been made in wireless ICs supporting this ground-breaking technology. Adding neurochemical pattern generation to extant sensing- only ICs substantively expands the utility of chemical sensing ICs, ultimately laying foundational work for future closed-loop devices. We submit that extending passive chemical measurements to the realm of high-precision, dynamic chemical control is consistent with the R03 scope of development of new research technology. The two specific aims of this proposal are to: (1) develop a neurochemical sensing IC supporting FSCV at a CFM with integrated electrical stimulation capability for neurochemical pattern generation; (2) test and characterize the IC. The engineering innovation is that IC architecture will precisely synchronize the timing of voltammetry and stimulus current generation to avoid temporal overlap and minimize the possibility of stimulus artifacts interfering with FSCV recordings, whenever the stimulator is activated via an external trigger. In addition to benchtop engineering assessment, functionality will be tested in vitro with flow injection analysis and in vivo with anesthetized rats, using diverse neurochemical patterns as templates. The conceptual innovation is transfer function-driven neurochemical pattern generation and subsequent verification of the fidelity of the generated profile by the stimulating-sensing IC. Selection of dopamine as the test analyte in this work is very judicious. Involved in important brain functions and debilitating neuropathologies, dopamine is amenable to FSCV detection, is the most studied neurotransmitter using microsensors, and has well-established transfer functions suitable for time- and amplitude-based pattern generation. Transferable to other neurotransmitters, microsensor strategies, and applications, we emphasize the general versatility of the proposed IC as a more wide-ranging device beyond these development tests with dopamine. Thus, in the long term, the proposed IC will provide an innovative and powerful addition to the neurobiology toolkit for investigating the neural underpinnings of behavior and disease symptoms, and could have additional clinical bearing by providing the framework for ultimately developing new neuromodulation devices for many human neuropathologies. PUBLIC HEALTH RELEVANCE: Neurochemical Pattern Generation with Smart Electrical Stimulation Pedram Mohseni1 and Paul A. Garris2 1 Case Western Reserve University 2 Illinois State University Relevance to Public Health: This project will develop an advanced integrated circuit for measuring and controlling neurotransmitter levels in the brain of laboratory animals. This technology will advance basic biomedical research and the development of neuroprostheses for treating human neuropathologies.